Thiazolyl amide derivatives

ABSTRACT

The present invention relates to novel compounds, to a process for their preparation and to their use as medicaments, in particular as antiviral medicaments.

The present invention relates to novel compounds, namely thiazolyl amidederivatives, to processes for their preparation and to their use asmedicaments, in particular as antiviral medicaments.

2-Aminothiazole-5-sulphonamides are known from the publication C.Ziegler et al., J. Org. Chem. 25, 1960, 1454-1455. Moreover, the GermanOffenlegungsschrift 2101640 describes N-thiazol-2-yl-amides and -ureashaving herbicidal action.

WO97/24343 relates to phenylthiazole derivatives havinganti-herpes-virus properties.

WO99/42455 likewise relates to phenylthiazole derivatives havinganti-herpes-virus properties.

WO99/47507 relates to 1,3,4-thiadiazole derivatives havinganti-herpes-virus properties.

The present invention relates to novel compounds which are thiazolylamide derivatives of the general formula (I):

in which

-   R¹ represents hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,    amino-(C₁-C₆)-alkyl or halogeno-(C₁-C₆)-alkyl,-   R² and R³ are identical or different and represent hydrogen,    (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl or biphenylaminocarbonyl, or-    represent (C₁-C₆)-alkyl which is optionally substituted by 1 to 3    substituents selected from the group consisting of    (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen, hydroxyl, amino,    tri-(C₁-C₆)-alkylsilyloxy, radicals of the formula-    in which R^(2′) represents hydrogen or (C₁-C₄)-alkyl,-    a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms    from the group consisting of S, N and O, where a nitrogen-containing    heterocycle may also be attached via the nitrogen atom,-    a 3- to 8-membered saturated or unsaturated nonaromatic heterocycle    having up to 3 heteroatoms from the group consisting of S, N and O,    which may optionally be attached via a nitrogen atom, and    (C₆-C₁₀)-aryl which for its part may be substituted by hydroxyl or    (C₁-C₆)-alkoxy, or-    represent a group of the formula-    in which R⁸ and R⁹ are identical to or different from one another    and represent hydrogen and (C₁-C₄)-alkyl, or-    represent a group of the formula-    in which R¹⁰ is the side-group of a naturally occurring α-amino    acid, or-    represent a group of the formula-    in which R¹¹ represents (C₁-C₄)-alkyl and R¹² represents hydrogen,    (C₁-C₄)-alkyl or represents a group of the formula-    in which R^(10′) is the side-group of a naturally occurring α-amino    acid, or    -   R² and R³ together with the nitrogen atom form a 5- or        6-membered saturated heterocycle which may optionally contain an        oxygen atom,    -   R⁴ represents hydrogen, (C₁-C₆)-acyl, (C₂-C₆)-alkenyl,        (C₃-C₈)-cycloalkyl, or    -   R⁴ represents (C₁-C₆)-alkyl which may optionally be substituted        by 1 to 3 substituents selected from the group consisting of        halogen, hydroxyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-acyl,        (C₁-C₆)-alkoxy, carboxyl,    -    in which R^(4′) represents hydrogen, —(OCH₂CH₂)_(n)OCH₂CH₃, in        which n is 0 or 1, phenoxy, (C₆-C₁₀)-aryl and —NR¹³R¹⁴,    -    in which R¹³ and R¹⁴ are identical or different and represent        hydrogen, (C₁-C₆)-acyl, (C₁-C₆)-alkyl, carbamoyl, mono- or        di-(C₁-C₆)-alkylamino-(C₁-C₆)-alkyl, mono- or        di-(C₁-C₆)-alkylaminocarbonyl, (C₆-C₁₀)-aryl or        (C₁-C₆)-alkoxycarbonyl, or    -    R¹³ and R¹⁴ together with the nitrogen atom form a 5- or        6-membered saturated heterocycle which may optionally contain a        further heteroatom from the group consisting of S and O or a        radical of the formula —NR¹⁵, and which may be substituted by        oxo,    -    in which        -   R¹⁵ represents hydrogen or (C₁-C₄)-alkyl, or        -   R⁴ represents (C₁-C₆)-alkyl which is substituted by a 5- or            6-membered aromatic, optionally benzo-fused heterocycle            having up to 3 heteroatoms from the group consisting of S, N            and O, where a nitrogen-containing heterocycle may also be            attached via the nitrogen atom, or which is substituted by        -   radicals of the formulae        -   in which        -   R¹⁶ represents hydrogen or (C₁-C₆)-alkyl,        -   R¹⁷ and R¹⁸ are identical or different and represent            hydrogen, (C₁-C₆)-alkyl or (C₆-C₁₀)-aryl, where            abovementioned (C₁-C₆)-alkyl and (C₆-C₁₀)-aryl may            optionally be substituted by 1 to 3 substituents selected            from the group consisting of hydroxyl, (C₁-C₆)-alkoxy and            halogen,    -   R⁵ represents hydrogen, (C₁-C₆)-alkyl, halogen, amino, mono- or        di-(C₁-C₆)-alkylamino or represents (C₁-C₆)-alkanoylamino,    -   R⁶ represents phenyl which may optionally be substituted by one        to three substituents selected from the group consisting of        -   halogen,        -   (C₆-C₁₀)-aryl which may optionally be substituted by 1 to 3            substituents selected from the group consisting of            (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,            (C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,            halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl,            carboxyl, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,            mono- or di-(C₁-C₆)-alkanoylamino,            (C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkylsulphoxy,            (C₁-C₆)-alkylsulphonyl, tri-(C₁-C₆)-alkylsilyloxy, a 3- to            8-membered saturated or unsaturated non-aromatic mono- or            bicyclic heterocycle having up to 3 heteroatoms from the            group consisting of S, N and O, which may optionally be            attached via a nitrogen atom, and/or cyano,        -   (C₁-C₆)-alkoxy,        -   (C₁-C₆)-alkoxycarbonyl,        -   (C₁-C₆)-alkylthio,        -   hydroxyl,        -   carboxyl,        -   partially fluorinated (C₁-C₆)-alkoxy having up to 6 fluorine            atoms,        -   (C₁-C₆)-alkyl which is optionally substituted by a radical            of the formula        -   a 5- or 6-membered aromatic heterocycle having up to 3            heteroatoms from the group consisting of S, N and O which            may optionally be attached via a nitrogen atom and which may            optionally be substituted by 1 to 3 substituents selected            from the group consisting of (C₁-C₆)-alkanoyl,            (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,            (C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,            halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl,            carboxyl, carbamoyl, aminocarbonyl, mono- or            di-(C₁-C₆)-alkylaminocarbonyl, mono- or            di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,            (C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsuphonyl, a 3- to            8-membered saturated or unsaturated nonaromatic mono- or            bicyclic heterocycle having up to 3 heteroatoms from the            group consisting of S, N and O which may optionally be            attached via a nitrogen atom, and/or cyano,        -   a 3- to 8-membered saturated or unsaturated nonaromatic            mono- or bicyclic heterocycle having up to 3 heteroatoms            from the group consisting of S, N and O, which may            optionally be attached via a nitrogen atom and which may            optionally be substituted by 1 to 3 substituents selected            from the group consisting of oxo, halogen, hydroxyl,            (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino,            (C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkyl and            hydroxy-(C₁-C₆)-alkyl,        -   (C₂-C₆)-alkenyl    -    and groups of the formulae        -   —OR¹⁹,        -   —NR²⁰R²¹ or —CO—NR²²R²³,        -   carbazole, dibenzofuran or dibenzothiophene,        -   xanthene or 9,10-dihydroacridine,    -    in which R¹⁹ is phenyl which for its part is optionally        substituted by a group of the formula —NR²⁴R²⁵    -    in which        -   R²⁴ and R²⁵ are identical or different and represent            hydrogen, (C₁-C₆)-alkyl or (C₁-C₆)-acyl, or        -   R¹⁹ represents (C₁-C₆)-alkyl which is optionally mono- to            trisubstituted by hydroxyl and/or halogen,        -   R²⁰ and R²¹ are identical or different and represent            hydrogen, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,            phenyl, (C₁-C₆)-acyl or (C₁-C₆)-alkyl,    -    where abovementioned (C₁-C₆)-alkyl is optionally substituted by        (C₁-C₆)-alkoxy, (C₁-C₆)-acyl, by phenyl or by a 5- or 6-membered        aromatic heterocycle having up to 3 heteroatoms from the group        consisting of S, N and O,    -    where abovementioned phenyl and abovementioned aromatic        heterocycle are optionally mono- to trisubstituted by identical        or different substituents from the group consisting of halogen        and hydroxyl, and    -    R²² and R²³ are identical or different and represent hydrogen        or (C₁-C₆)-alkyl,    -    and R⁷ may have the meaning of R⁵ and may be identical to or        different from R⁵,        and their salts.

Physiologically acceptable salts of the compounds according to theinvention can be, for example, salts of the substances according to theinvention with mineral acids, carboxylic acids or sulphonic acids.Particular preference is given, for example, to salts with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid, or benzoic acid.

Salts which may furthermore be mentioned are salts with customary bases,such as, for example, alkali metal salts (for example sodium orpotassium salts), alkaline earth metal salts (for example calcium ormagnesium salts) or ammonium salts, derived from ammonia or organicamines, such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine or methylpiperidine.

Depending on the substitution pattern, the compounds according to theinvention can exist in stereoisomeric forms which either behave as imageand mirror image (enantiomers), or which do not behave as image andmirror image (diastereomers). The invention relates both to theenantiomers or diastereomers and their respective mixtures. Like thediastereomers, the racemic forms can be separated into thestereoisomerically uniform components in a known manner.

The scope of the invention includes those compounds which are onlyconverted into the actual active compounds of the formula (I) onceinside the body (so-called prodrugs).

(C₁-C₆)-Alkyl advantageously represents a straight-chain or branchedalkyl radical having from 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkyl radical having 1 to 4 carbon atoms(C₁-C₄). Examples which may be mentioned are:

-   methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,    n-pentyl and n-hexyl. Particular preference is given to a    straight-chain or branched alkyl radical having 1 to 3 carbon atoms    ((C₁-C₃)-alkyl).

Halogeno-(C₁-C₆)-alkyl advantageously represents a (C₁-C₆)-alkyl groupwhich can be defined as above and which has 1 to 3 halogen atoms, namelyF, Cl, Br and/or I, preferably chlorine or fluorine, as substituents;examples which may be mentioned are trifluoromethyl, fluoromethyl, etc.

Hydroxy-(C₁-C₆)-alkyl advantageously represents a (C₁-C₆)-alkyl groupwhich can be defined as above and which has 1 to 3 hydroxyl groups assubstituents; examples which may be mentioned are hydroxymethyl etc.

(C₁-C₆)-Alkenyl in the context of the invention advantageouslyrepresents a straight-chain or branched alkenyl radical having 2 to 6carbon atoms. Examples which may be mentioned are: ethenyl,n-prop-2-en-1-yl and n-but-2-en-1-yl. Preference is given to astraight-chain or branched alkenyl radical having 2 to 4 carbon atoms.

(C₁-C₆)-Alkoxy advantageously represents a straight-chain or branchedalkoxy radical having 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms(C₁-C₄). Examples which may be mentioned are: methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Particularpreference is given to a straight-chain or branched alkoxy radicalhaving 1 to 3 carbon atoms-(C₁-C₃).

Halogeno-(C₁-C₆)-alkoxy advantageously represents mono- orpolyhalogenated (C₁-C₆)-alkoxy. With respect to the (C₁-C₆)-alkoxymoiety and the definition of halogen, reference is made to the abovedefinition. Halogeno-(C₁-C₆)-alkoxy includes, for example, partiallymono- or polychlorinated and/or -fluorinated or -perfluorinated(C₁-C₆)-alkoxy, such as trifluoromethoxy, fluoromethoxy, chloromethoxy,pentafluoroethoxy, trifluoromethylmethoxy, etc.

Partially fluorinated (C₁-C₆)-alkoxy having up to 6 fluorine atomsadvantageously represents a straight-chain or branched alkoxy radicalhaving 1 to 6 carbon atoms which may be substituted by 1 to 6,preferably 1 to 4, more preferably 1 to 3, fluorine atoms. Preference isgiven to a straight-chain or branched alkoxy radical having 1 to 4carbon atoms and 1 to 4 fluorine atoms. Examples which may be mentionedare: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy andn-hexoxy, which in each case have 1 to 4 fluorine atoms. Particularpreference is given to (1,3-difluoroprop-2-yl)-oxy and1,1,2,2-tetrafluorethoxy.

(C₁-C₆)-Alkylthio advantageously represents a straight-chain or branchedalkylthio radical having 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkylthio radical having 1 to 4 carbon atoms(C₁-C₄). Examples which may be mentioned are: methylthio, ethylthio,n-propylthio, isopropylthio, tert-butylthio, n-pentylthio andn-hexylthio. Particular preference is given to a straight-chain orbranched alkylthio radical having 1 to 3 carbon atoms (C₁-C₃)-alkylthio.

(C₁-C₆)-Alkoxycarbonyl advantageously represents a straight-chain orbranched alkoxycarbonyl radical having 1 to 6 carbon atoms. Preferenceis given to a straight-chain or branched alkoxycarbonyl radical having 1to 4 carbon atoms (C₁-C₄). Examples which may be mentioned are:methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyland tert-butoxycarbonyl. Particular preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms (C₁-C₄).

Mono- or di-(C₁-C₆)-alkylaminocarbonyl in the context of the inventionadvantageously represents a carbamoyl group (H₂N—CO—), in which one orboth hydrogen atoms are replaced by a (C₁-C₆)-alkyl group. With respectto the definition of the (C₁-C₆)-alkyl group, reference is made to theabove explanation of (C₁-C₆)-alkyl. Examples which may be mentioned aremethylaminocarbonyl, dimethylamino, etc.

Mono- or di-(C₁-C₆)-acylamino in the context of the inventionadvantageously represents an amino group (H₂N—) in which one or bothhydrogen atoms are replaced by a (C₁-C₆)-acyl group. With respect to thedefinition of the (C₁-C₆)-acyl group, reference is made to the aboveexplanation of (C₁-C₆)-acyl. An example which may be mentioned is(C₁-C₆)-alkanoyl, as mentioned in the definition of (C₁-C₆)-acyl.

(C₁-C₆)-Alkylsulphoxy advantageously represents a (C₁-C₆)-alkyl-S(═O)—group, where, with respect to the (C₁-C₆)-alkyl group, reference can bemade to the relevant definition above.

(C₁-C₆)-Alkylsulphonyl advantageously represents a (C₁-C₆)-alkyl-SO₂group where, with respect to the (C₁-C₆)-alkyl group, reference can bemade to the relevant definition above.

(C₆-C₁₀)-Aryl generally represents an aromatic radical having 6 to 10carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C₁-C₆)-Acyl in the context of the invention advantageously represents astraight-chain or branched acyl radical having 1 to 6 carbon atoms.Examples which may be mentioned are: formyl, acetyl, ethanoyl,propanoyl, isopropanoyl, butanoyl, isobutanoyl and pentanoyl. Preferenceis given to a straight-chain or branched acyl radical having 1 to 4carbon atoms. Particular preference is given to acetyl and ethanoyl.

(C₃-C₈)-Cycloalkyl in the context of the invention representscyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl orcyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl may be mentioned asbeing preferred. The meaning of (C₃-C₆)-cycloalkyl is correspondinglyadvantageously cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl.

Halogen in the context of the invention generally represents fluorine,chlorine, bromine and iodine. Preference is given to fluorine, chlorineand bromine. Particular preference is given to fluorine and chlorine.

(C₁-C₆)-Alkanoyl in the context of the invention represents formyl and(C₁-C₅)-alkylcarbonyl groups, where (C₁-C₅)-alkyl may be astraight-chain or branched alkyl group having 1 to 5 carbon atoms, forexample acetyl, propionyl, butyryl, pentanoyl.

A 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe group consisting of S, O and N represents, for example, pyridyl,pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, oxazolyl orimidazolyl. Preference is given to pyridyl, furyl, thiazolyl andN-triazolyl.

A 5- or 6-membered aromatic benzo-fused heterocycle having up to 3heteroatoms from the group consisting of S, O and N represents, forexample, benzimidazolyl.

A 5- or 6-membered saturated heterocycle attached via a nitrogen atom,which can be formed from two substituent groups together with thenitrogen atom to which they are attached, and which may optionallycontain a further heteroatom from the group consisting of S and O or aradical of the formula —NR¹⁵, in which R¹⁵ is as defined above,generally represents, in the context of the invention, morpholinyl,piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl orpyrrolidinyl. Particular preference is given to morpholinyl,piperidinyl, pyrrolidinyl and thiomorpholinyl.

A 3- to 8-membered saturated or unsaturated nonaromatic heterocyclewhich is optionally attached via a nitrogen atom and which has up to 3heteroatoms from the group consisting of S, N and O includes, forexample, the abovementioned 5- or 6-membered saturated heterocycleswhich are attached via a nitrogen atom, and also 3-, 7- and 8-memberedheterocycles, such as, for example, aziridines (for example1-azacyclopropan-1-yl), azetidines (for example 1-azacyclobutan-1-yl)and azepines (for example 1-azepan-1-yl). The unsaturatedrepresentatives may contain 1 or 2 double bonds in the ring.

The side-group of a naturally occurring α-amino acid in the meaning ofR¹⁰ includes, for example: hydrogen (glycine), methyl (alanine),propan-2-yl (valine), 2-methyl-propan-1-yl (leucine),1-methyl-propan-1-yl (isoleucine), a propan-1,3-diyl group which isattached to the nitrogen atom of the amino group (proline), a2-hydroxypropane-1,3-diyl group which is attached to the nitrogen atomof the amino group (hydroxyproline), a group of the formula

(tryptophan), a benzyl group (phenylalanine), a methylthioethyl group(methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine),1-hydroxy-ethan-1-yl (threonine), mercaptomethyl (cysteine),carbamoylmethyl (asparagine), carbamoylethyl (glutamine), carboxymethyl(aspartic acid), carboxyethyl (glutamic acid), 4-aminobutan-1-yl(lysine), 3-guanidinopropan-1-yl (arginine), imidazol-4-ylmethyl(histidine), 3-ureidopropan-1-yl (citrulline), mercaptoethyl(homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxybutan-1-yl(hydroxylysine), 3-amino-propan-1-yl (ornithine), etc.

In a further embodiment, the invention relates to compounds of thegeneral formula (I) according to Claim 1:

in which

-   R¹ represents hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,    amino-(C₁-C₆)-alkyl or halogeno-(C₁-C₆)-alkyl,-   R² and R³ are identical or different and represent hydrogen,    (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkyl or biphenylaminocarbonyl, or    represent (C₁-C₆)-alkyl which is optionally substituted by 1 to 3    substituents selected from the group consisting of    (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen, hydroxyl, amino,    radicals of the formula    a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms    from the group consisting of S, N and O, where a nitrogen-containing    heterocycle may also be attached via the nitrogen atom,    a 3- to 8-membered saturated or unsaturated nonaromatic heterocycle    having up to 3 heteroatoms from the group consisting of S, N and O,    which may optionally be attached via a nitrogen atom, and    (C₆-C₁₀)-aryl, which for its part may be substituted by hydroxyl or    (C₁-C₆)-alkoxy, or    represent a group of the formula    in which R⁸ and R⁹ are identical to or different from one another    and represent hydrogen and (C₁-C₄)-alkyl, or    represent a group of the formula    in which R¹⁰ is the side-group of a naturally occurring α-amino    acid, or    represent a group of the formula    in which R¹¹ represents (C₁-C₄)-alkyl and R¹² represents hydrogen,    (C₁-C₄)-alkyl or represents a group of the formula    in which R^(10′) is the side-group of a naturally occurring α-amino    acid, or-   R² and R³ together with the nitrogen atom form a 5- or 6-membered    saturated heterocycle which may optionally contain an oxygen atom,-   R⁴ represents hydrogen, (C₁-C₆)-acyl, (C₂-C₆)-alkenyl,    (C₃-C₈)-cycloalkyl, or-   R⁴ represents (C₁-C₆)-alkyl which may optionally be substituted by 1    to 3 substituents selected from the group consisting of halogen,    hydroxyl, (C₁-C₆)-acyl, (C₁-C₆)-alkoxy, —(OCH₂CH₂)_(n)OCH₂CH₃, in    which n is 0 or 1, phenoxy, (C₆-C₁₀)-aryl and —NR¹³R¹⁴,    -   in which R¹³ and R¹⁴ are identical or different and represent        hydrogen, (C₁-C₆)-acyl, (C₁-C₆)-alkyl, carbamoyl, mono- or        di-(C₁-C₆)-alkylamino-(C₁-C₆)-alkyl, mono- or        di-(C₁-C₆)-alkylaminocarbonyl, (C₆-C₁₀)-aryl or        (C₁-C₆)-alkoxycarbonyl, or        -   R¹³ and R¹⁴ together with the nitrogen atom form a 5- or            6-membered saturated heterocycle which may optionally            contain a further heteroatom from the group consisting of S            and O or a radical of the formula —NR¹⁵ and which may be            substituted by oxo,        -   in which R¹⁵ represents hydrogen or (C₁-C₄)-alkyl, or-   R⁴ represents (C₁-C₆)-alkyl which is substituted by a 5- or    6-membered aromatic, optionally benzo-fused heterocycle having up to    3 heteroatoms from the group consisting of S, N and O, where a    nitrogen-containing heterocycle may also be attached via the    nitrogen atom, or which is substituted by radicals of the formulae    -   in which    -   R¹⁶ represents hydrogen or (C₁-C₆)-alkyl,    -   R¹⁷ and R¹⁸ are identical or different and represent hydrogen,        (C₁-C₆)-alkyl or (C₆-C₁₀)-aryl, where abovementioned        (C₁-C₆)-alkyl and (C₆-C₁₀)-aryl may optionally be substituted by        1 to 3 substituents selected from the group consisting of        hydroxyl, (C₁-C₆)-alkoxy and halogen,-   R⁵ represents hydrogen, (C₁-C₆)-alkyl, halogen, amino, mono- or    di-(C₁-C₆)-alkylamino or represents (C₁-C₆)-alkanoylamino,-   R⁶ represents phenyl which may optionally be substituted by one to    three substituents selected from the group consisting of    -   halogen,    -   (C₆-C₁₀)-aryl which may optionally be substituted by 1 to 3        substituents selected from the group consisting of        (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,        (C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,        halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl,        carboxyl, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,        mono- or di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,        (C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl,        tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or        unsaturated nonaromatic mono- or bicyclic heterocycle having up        to 3 heteroatoms from the group consisting of S, N and O, which        may optionally be attached via a nitrogen atom, and/or cyano,    -   (C₁-C₆)-alkoxy,    -   (C₁-C₆)-alkoxycarbonyl,    -   (C₁-C₆)-alkylthio,    -   hydroxyl,    -   carboxyl,    -   partially fluorinated (C₁-C₆)-alkoxy having up to 6 fluorine        atoms,    -   (C₁-C₆)-alkyl which is optionally substituted by a radical of        the formula    -   a 5- or 6-membered aromatic heterocycle having up to 3        heteroatoms from the group consisting of S, N and O which may        optionally be attached via a nitrogen atom and which may        optionally be substituted by 1 to 3 substituents selected from        the group consisting of (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy,        (C₁-C₆)-alkyl, halogen, (C₁-C₆)-alkoxycarbonyl, nitro,        halogeno-(C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkoxy, amino,        (C₁-C₆)-alkylthio, hydroxyl, carboxyl, carbamoyl, mono- or        di-(C₁-C₆)-alkylaminocarbonyl, mono- or        di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,        (C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsuphonyl, a 3- to 8-membered        saturated or unsaturated nonaromatic mono- or bicyclic        heterocycle having up to 3 heteroatoms from the group consisting        of S, N and O which may optionally be attached via a nitrogen        atom, and/or cyano,    -   a 3- to 8-membered saturated or unsaturated nonaromatic mono- or        bicyclic heterocycle having up to 3 heteroatoms from the group        consisting of S, N and O, which may optionally be attached via a        nitrogen atom and which may optionally be substituted by 1 to 3        substituents selected from the group consisting of oxo, halogen,        hydroxyl, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonylamino,        (C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkyl and hydroxy-(C₁-C₆)-alkyl,    -   and groups of the formulae        -   —OR¹⁹,        -   —NR²⁰R²¹ or —CO—NR²²R²³,        -   in which R¹⁹ is phenyl which for its part is optionally            substituted by a group of the formula —NR²⁴R²⁵        -   in which            -   R²⁴ and R²⁵ are identical or different and represent                hydrogen, (C₁-C₆)-alkyl or (C₁-C₆)-acyl,            -    or            -   R¹⁹ represents (C₁-C₆)-alkyl which is optionally mono-                to trisubstituted by hydroxyl and/or halogen,    -   R²⁰ and R²¹ are identical or different and represent hydrogen,        carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, phenyl,        (C₁-C₆)-acyl or (C₁-C₆)-alkyl,    -    where abovementioned (C₁-C₆)-alkyl is optionally substituted by        (C₁-C₆)-alkoxy, (C₁-C₆)-acyl, by phenyl or by a 5- or 6-membered        aromatic heterocycle having up to 3 heteroatoms from the group        consisting of S, N and O,    -    where abovementioned phenyl and abovementioned aromatic        heterocycle are optionally mono- to trisubstituted by identical        or different substituents from the group consisting of halogen        and hydroxyl, and    -   R²² and R²³ are identical or different and represent hydrogen or        (C₁-C₆)-alkyl,    -   and R⁷ may have the meaning of R⁵ and may be identical to or        different from R⁵,        and their salts.

In a preferred embodiment, the invention relates to compounds of thegeneral formula (I) in which R¹ represents hydrogen or (C₁-C₆)-alkyl.

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I) in which R² and R³ each independently representhydrogen or (C₁-C₆)-alkyl.

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I) in which R⁴ represents hydrogen or(C₁-C₆)-alkyl.

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I) in which R⁵ represents hydrogen.

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I) in which

-   R⁶ represents phenyl which may optionally be substituted by one to    three substituents selected from the group consisting of    -   halogen,    -   (C₆-C₁₀)-aryl which may optionally be substituted by 1 to 3        substituents selected from the group consisting of        (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,        (C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,        halogeno-(C₁-C₆)-alkoxy, amino, hydroxyl, mono- or        di-(C₁-C₆)-alkylamino, mono- or di-(C₁-C₆)-alkanoylamino,        (C₁-C₆)-alkoxycarbonylamino, and/or cyano,    -   a 5- or 6-membered aromatic heterocycle having up to 3        heteroatoms from the group consisting of S, N and O, which may        optionally be attached via a nitrogen atom and which may        optionally be substituted by 1 or 2 halogen atoms.

In a further preferred embodiment, the invention relates to compoundshaving the following formula:

in which

-   R¹, R², R³, R⁴, R⁵ and R⁷ are each as defined in Claim 1,-   R²⁶ and R²⁷ are identical or different and represent hydrogen,    halogen, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylthio,    hydroxyl, carboxyl, partially fluorinated (C₁-C₆)-alkoxy having up    to 6 fluorine atoms, (C₁-C₆)-alkyl, a group of the formula —OR¹⁹,    —NR²⁰R²¹ or —CO—NR²²R²³, in which-   R¹⁹ represents phenyl which for its part is optionally substituted    by a group of the formula —NR²⁴R²⁵,    in which-   R²⁴ and R²⁵ are identical or different and represent hydrogen,    (C₁-C₆)-alkyl or (C₁-C₆)-acyl, or-   R¹⁹ represents (C₁-C₆)-alkyl which is optionally mono- to    trisubstituted by hydroxyl and/or halogen,-   R²⁰ and R²¹ are identical or different and represent hydrogen,    carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, phenyl,    (C₁-C₆)-acyl or (C₁-C₆)-alkyl,-    where abovementioned (C₁-C₆)-alkyl is optionally substituted by    (C₁-C₆)-alkoxy, (C₁-C₆)-acyl, phenyl or by a 5- or 6-membered    aromatic heterocycle having up to 3 heteroatoms from the group    consisting of S, N and O,-    where abovementioned phenyl and abovementioned aromatic heterocycle    are optionally mono- to trisubstituted by identical or different    substituents from the group consisting of halogen and hydroxyl, and-   R²² and R²³ are identical or different and represent hydrogen or    (C₁-C₆)-alkyl,-   R²⁸ represents (C₆-C₁₀)-aryl, which may optionally be substituted by    1 to 3 substituents selected from the group consisting of    (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,    (C₁-C₆)-alkoxycarbonyl, nitro, halogen-(C₁-C₆)-alkyl,    halogen-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl,    carboxyl, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono-    or di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,    (C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl,    tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or    unsaturated nonaromatic mono- or bicyclic heterocycle having up to 3    heteroatoms from the group consisting of S, N and O, which may    optionally be attached via a nitrogen atom, and/or cyano, or-   R²⁸ represents a 5- or 6-membered aromatic heterocycle having up to    3 heteroatoms from the group consisting of S, N and O, which may    optionally be attached via a nitrogen atom and which may optionally    be substituted by 1 to 3 substituents selected from the group    consisting of (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl,    halogen, (C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,    halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl,    carboxyl, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono-    or di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,    (C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl, a 3- to 8-membered    saturated or unsaturated nonaromatic mono- or bicyclic heterocycle    having up to 3 heteroatoms from the group consisting of S, N and O,    which may optionally be attached via a nitrogen atom, and/or cyano,    and their salts.

Particular preference is, for example, given to the compoundN-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-2-[1,1′-biphenyl]4-yl-N-methylacetamideof the formula:

to the compoundN-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-2-(2′-fluoro[1,1′-biphenyl]-4-yl)-N-methylacetamideof the formula:

and to the compoundN-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamideof the formula:

and to pharmaceutically acceptable salts thereof.

The invention furthermore relates to compounds of the general formula(IV)

in which

-   R¹, R⁴, R⁵, R⁶ and R⁷ each have the meaning given for the    formula (I) and D represents a halogen atom.

The invention furthermore relates to processes for preparing thecompounds of the general formula (I), characterized in that

-   [A] compounds of the general formula (II)    -   in which    -   R¹, R², R³ and R⁴ are each as defined above,    -   are reacted with compounds of the general formula (III)    -   in which    -   A represents a leaving group, such as, for example, halogen,        preferably chlorine, or hydroxyl, and R⁵, R⁶ and R⁷ are each as        defined above, in inert solvents, if appropriate in the presence        of a base and/or an auxiliary, to give compounds of the formula        (I),-   [B] compounds of the general formula (IV)    -   in which    -   R¹, R⁴, R⁵, R⁶ and R⁷ are each as defined above and D represents        a halogen atom, preferably chlorine, are reacted with amines of        the general formula (V)        HNR²R³  (V),    -   in which    -   R² and R³ are each as defined above, in inert solvents, to give        compounds of the formula (I),-   [C] compounds of the general formula (X)    -   in which    -   R¹, R², R³, R⁴, R⁵, R⁷, R²⁶ and R²⁷ are each as defined above        and E represents trifluoromethanesulphonate or halogen,        preferably bromine or iodine, are reacted with boronic acids or        stannanes of the general formula (XI)        R²⁸M  (XI),    -   in which    -   R²⁸ is as defined above and M may be, for example, a        tri-(C₁-C₆)-alkylstannyl group, such as a trimethylstannyl        group, or a boronic acid group, in inert solvents in the        presence of palladium catalysts, for example        tetrakis(triphenylphosphane) palladium(0), if appropriate in the        presence of a base, for example potassium phosphate, at        temperatures of 50-140° C., to give compounds of the formula        (XIV)    -   and-   [D] compounds of the general formula (XII)    -   in which    -   R¹, R², R³, R⁴, R⁵, R⁷, R²⁶ and R²⁷ are each as defined above        and M is as defined above, are reacted with        trifluoromethanesulphonates or halides of the general formula        (XIII):        R²⁸E  (XIII),    -   in which    -   R²⁸ is as defined above and E is as defined above, in inert        solvents in the presence of palladium catalysts, for example        tetrakis(triphenylphosphane)palladium (0), if appropriate in the        presence of a base, for example potassium phosphate, at        temperatures of 50-140° C., to give compounds of the formula        (XIV).

The process [A] according to the invention can be illustrated in anexemplary manner by the following equation:

The abbreviations denote:

-   HOBt: 1-hydroxy-1H-benzotriazole-   EDC: N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl-   DMF: N,N-dimethylformamide

The process [C] according to the invention can be illustrated in anexemplary manner by the following equation:

The abbreviation denotes:

-   DMF: N,N-dimethylformamide

The process [D] according to the invention can be illustrated in anexemplary manner by the following equation:

The abbreviation denotes:

-   DMF: N,N-dimethylformamide

Suitable solvents for the processes [A], [B], [C] and [D] are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or mineral oilfractions, or halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, dimethylsulphoxide, dimethylformamide (DMF) or acetonitrile. It is also possibleto use mixtures of the solvents mentioned. Preference is given to DMF.

Suitable bases for use in the process [A] according to the inventionare, in general, inorganic or organic bases. These preferably includeorganic amines (trialkyl(C₁-C₆)amines), such as triethylamine, orheterocycles, such as 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,N-methylmorpholine or N-methylpiperidine or morpholine. Preference isgiven to triethylamine.

Suitable auxiliaries are dehydrating or coupling reagents which areknown per se, such as, for example, carbodiimides, such asdiisopropylcarbodiimide, dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), or carbonylcompounds, such as carbonyldiimidazole (CDI) or isobutyl chloroformate,or 1,2-oxazolium compounds, such as2-ethyl-5-phenyl-1,2-oxazolium-3′-sulphonate, or phosphorus compounds,such as propanephosphonic anhydride, diphenylphosphoryl azide,benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), or uronium compounds, such asO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or methanesulphonyl chloride, if appropriate in the presence ofauxiliaries, such as N-hydroxysuccinimide or N-hydroxybenzotriazole.

In general, the base is employed in an amount of from 0.05 mol to 10mol, preferably from 1 mol to 2 mol, based on 1 mol of the compound ofthe formula (III).

The processes according to the invention are generally carried out in atemperature range of from −50° C. to +100° C., preferably from −30° C.to +60° C.

The processes according to the invention are generally carried out atatmospheric pressure. However, it is also possible to carry out theprocesses at elevated pressure or at reduced pressure (for example in arange of from 0.5 to 5 bar).

The compounds of the general formula (II) can be prepared, for example,by converting compounds of the general formula (VI)

in which

-   R¹ is as defined above-   by reaction with the system chlorosulphonic acid/SOCl₂ into the    compounds of the general formula (VII)    in which-   R¹ is as defined above,-   then, using amines of the general formula (V)    HNR²R³  (V)    in which-   R² and R³ are each as defined above-   in inert solvents, preparing the compounds of the general formula    (VIII)    in which-   R¹, R² and R³ are each as defined above-   and, in a last step, carrying out a reaction with amines of the    general formula (IX)    H₂N—R^(4′)  (IX)    in which-   R^(4′) has the meaning of R⁴ given above and is identical to or    different from R⁴, but is not hydrogen,    in inert solvents and in the presence of a base.

The reaction with chlorosulphonic acid/SO₂Cl is initially carried out atroom temperature and then at the reflux temperature of the ether inquestion.

The reaction is generally carried out under atmospheric pressure.However, it is also possible to carry out the process at elevatedpressure or at reduced pressure (for example in a range of from 0.5 to 5bar).

Suitable solvents for the reaction with the amines of the generalformula (V) are alcohols, such as, for example, methanol, ethanol,propanol and isopropanol. Preference is given to methanol.

The reaction with the amines of the general formula (V) is initiallycarried out at room temperature and then at the reflux temperature ofthe ether in question.

The reaction is generally carried out at atmospheric pressure. However,it is also possible to carry out the process at elevated pressure or atreduced pressure (for example in a range of from 0.5 to 5 bar).

The reaction with the compounds of the general formula (IX) is carriedout in ethers, such as, for example, Methyl ether, dioxane,tetrahydrofuran or glycol dimethyl ether. Preference is given tomethanol.

Suitable for use as bases are, in general, inorganic or organic bases.These preferably include organic amines (tri(C₁-C₆)alkylamines, such astriethylamine), or heterocycles, such as 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. Preference is given totriethylamine.

In general, the base is employed in an amount of from 0.05 to 10 mol,preferably from 1 mol to 2 mol, based on 1 mol of the compound of theformula (VIII).

Some of the compounds of the general formula (VI) are known, or they canbe prepared by customary methods [cf. Hantzsch, Chem. Ber. 1927, 60,2544].

The compounds of the general formulae (VII) and (VIII) are novel and canbe prepared as described above.

Amines of the general formulae (V) and (IX) are known.

Compounds of the general formula (III) are known or can be prepared byprocesses known from the literature.

Biphenylmethylcarboxylic acid or biphenylacetic acid derivatives of theformula (III) can be prepared in a manner known per se bytransition-metal-catalysed, for example palladium-catalysed, couplingreactions, such as, for example, the Suzuki or Stille coupling. Thepyridylphenylmethylcarboxylic acid derivatives of the formula (III) areknown from the literature (see, for example, M. Artico et al. in Eur. J.Med. Chem. (1992) 27, 219-228), or they can be prepared by processesknown per se. The reaction schemes A, B, C and D below illustrate, in anexemplary manner, the synthesis of biphenylacetic acid derivatives fromthe corresponding boronic acids and the synthesis of pyridylphenylaceticacid derivatives from the corresponding stannyl compounds:

Compounds of the formula (III) in which R⁵ and R⁷ are fluorine, forexample, can be prepared by the process shown in the reaction schemebelow:

The fluorination with DAST (N,N-diethylaminosulphur trifluoride) iscarried out in accordance with J. Fluor. Chem. 61, 1993, 117.

The invention furthermore relates to the use of the compounds of theformula (I) as medicaments.

The invention furthermore relates to a pharmaceutical composition whichcomprises a compound of the general formula (I) in a mixture with atleast one pharmaceutically acceptable carrier or excipient.

The invention furthermore relates to the use of a compound of thegeneral formula (I) for preparing a medicament, in particular amedicament for the treatment and/or prevention of viral infections, suchas herpes viruses, in particular Herpes simplex viruses.

The invention furthermore relates to the use ofN-[5-(aminosulphonyl)-1,3-thiazol-2-yl]acetamide derivatives, preferablyN-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-phenylacetamide derivatives,more preferablyN-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-[1,1′-biphenyl]-4-ylacetamidederivatives, for preparing medicaments, in particular to the use of thederivatives mentioned for preparing compositions for the treatmentand/or prevention of viral infections in humans or animals, such asinfections caused by herpes viruses, in particular by Herpes simplexviruses. Here, N-[5-(aminosulphonyl)-1,3-thiazol-2-yl]acetamidederivatives, N-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-phenylacetamidederivatives andN-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-[1,1′-biphenyl]-4-ylacetamidederivatives are to be understood as meaning those compounds which arederived from N-[5-(aminosulphonyl)-1,3-thiazol-2-yl]acetamide,N-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-phenylacetamide andN-[5-(aminosulphonyl)-1,3-thiazol-2-yl]-2-[1,1′-biphenyl]-4-ylacetamideby the substitution of one or more hydrogen atoms.

The compounds of the general formula (I) according to the inventionexhibit an unforeseeable surprising spectrum of action. They exhibit anantiviral action against representatives of the Herpes viridae group,particularly against Herpes simplex viruses (HSV). They are thussuitable for the treatment and prophylaxis of disorders which are causedby herpes viruses, in particular disorders which are caused by Herpessimplex viruses.

In Vitro Activity

Viruses and Cells:

HSV (HSV-1 Walki, HSV-1F or HSV-2G) was cultivated on Vero cells (ATCCCCL-81) under the following conditions: The cells were grown in M199medium (5% foetal calf serum, 2 mM glutamine, 100 IU/ml penicillin, 100μg/ml streptomycin) in cell culture bottles at 37° C. and 5% CO₂. Thecells were splitted twice per week, in each case 1:4. For the infection,the medium was removed, the cells were washed with Hank's solution,detached using 0.05% trypsin, 0.02% EDTA (Seromed L2143) and incubatedat a density of 4×10⁵ cells per ml under the abovementioned conditionsfor 24 hours. The medium was then removed and the virus solution wasadded at an m.o.i of <0.05 in a volume of 2 ml per 175 cm² of surface.The medium was incubated under the conditions mentioned for one hour andthen made up to a volume of 50 ml per 175 cm² bottle. 3 days after theinfection, the cultures showed clear signs of a cytopathic effect. Thevirus was released by freezing (−80° C.) and thawing (37° C.) thecultures twice. Cell debris was removed by centrifugation (300 g, 10min, 4° C.) and the supernatant was frozen down in aliquots at −80° C.

The virus titre was determined using a plaque assay. To this end, Verocells were seeded in 24-well plates at a density of 4×10⁵ cells per welland, after 24 hours of incubation (37° C., 5% CO₂) infected withdilutions of the virus stock of from 10⁻² to 10⁻¹² (100 μl of inoculum).1 hour after the infection, the medium was removed and the cells werecovered with 1 ml of overlay medium (0.5% methylcellulose, 0.22% sodiumbicarbonate, 2 mM glutamine, 100 IU/ml penicillin, 100 μg/mlstreptomycin, 5% foetal calf serum in MEM-Eagle medium with Earl's salt)and incubated for 3 days. The cells were then fixated using 4% formalinefor 1 hour, washed with water, stained with Giemsa (Merck) for 30 minand then washed and dried. Using a plaque viewer, the virus titre wasdetermined. The virus stocks used for the experiments had a titre of1×10⁶/ml-1×10⁸/ml.

The anti-HSV action was determined in a screening test system in 96-wellmicrotitre plates using various cell lines of neuronal, lymphoid andepithelial origin, such as, for example, Vero (kidney cell line of thegreen monkey), MEF (murine embryonal fibroblasts), HELF (humaneembryonal fibroblasts), NT2 (humane neuronal cell line) or Jurkat(humane lymphoid T-cell line). The effect of the substances on thespreading of the cytopathogenic effect was determined in comparison tothe reference substance acyclovir-sodium (Zovirax^(R)), a clinicallyapproved anti-herpes chemotherapeutic.

The substances (50 mM), dissolved in DMSO (dimethyl sulphoxide), areexamined on microtitre plates (for example 96-well MTP) in finalconcentrations of 250-0.5 μM (micromolar) in two replications (4substances/plate). In the case of potent substances, the dilutions arecontinued for several plates up to 0.5 pM (picomolar). Also examined aretoxic and cytostatic effects of the substances. After an appropriatedilution of the substances (1:2) on the microtitre plate in medium, asuspension of cells (1×10⁴ cells per well) such as, for example, of Verocells in M199 (medium 199) with 5% foetal calf serum, 2 mM glutamine andoptionally 100 IU/ml penicillin and 100 μg/ml streptomycin or of MEFcells in EMEM (Eagle's Minimum Essential Medium) with 10% foetal calfserum, 2 mM glutamine and optionally 100 IU/ml penicillin and 100 μg/mlstreptomycin, or of HELF cells in EMEM with 10% foetal calf serum, 2 mMglutamine and optionally 100 IU/ml penicillin and 100 μg/mlstreptomycin, or of NT2- and Jurkat cells in DMEM (4.5 mg/l glucose pluspyridoxin) with 10% foetal calf serum, 2 mM glutamine, 1 mM sodiumpyruvate, non-essential amino acids and optionally 100 IU/ml penicillinand 100 μg/ml streptomycin is added to each well and the cells in therelevant wells are infected with an appropriate amount of virus (HSV-1 For HSV-2 G having an m.o.i (multiplicity of infection) of 0.0025 forHELF, Vero and MEF cells and an m.o.i of 0.1 for NT2 and Jurkat cells).The plates are then incubated at 37° C. in a CO₂ incubator (5% CO₂) forseveral days. After this time, the cell lawn of, for example, Vero cellsin the substance-free virus controls, starting from 25 infectioncentres, is completely destroyed or lysed by the cytopathogenic effectof the HSV viruses (100% CPE). The plates are initially evaluatedvisually using a microscope and then analysed using a fluorescent dye.To this end, the cell supernatant of all wells of the MTP is aspiratedand the wells are filled with 200 μl of PBS wash solution. The PBS isthen aspirated and all the wells are filled with 200 μl of fluorescentdye solution (fluorescein diacetate, 10 μg/ml in PBS). After anincubation time of 30-90 min, the test plates are read in a fluorescencedetector at an excitation wavelength of 485 nm and an emissionwavelength of 538 nm.

The results for some compounds are summarized in the table below.

TABLE Example IC50 HSV-1 F/Vero IC50 HSV-2 G/Vero 14 0.1 μM 0.75 μM 57<0.01 μM <0.01 μM 8 0.1 μM 0.1 μM 23 0.03 μM 0.1 μM 38 0.05 μM 0.016 μM87 <0.01 μM <0.01 μM 126 0.01 μM 0.1 μM Zovirax 1 μM 3 μM(aciclovir-sodium)

Here, IC₅₀ is the half-maximal fluorescence intensity with respect tothe non-infected cell control (100% value). The IC₅₀ value can also bereferenced to a suitable active compound control (see description of theassay: infected cells in the presence of suitable concentrations of asubstance having anti-herpes action, such as, for example, Zovirax 20μM). This active compound control reaches fluorescence intensities ofabout 85 to 95% with respect to the cell control.

Preference is given to N-[5-(aminosulphonyl)-1,3-thiazol-2-yl]acetamidederivatives according to the invention whose IC₅₀ (HSV-1 F/Vero) in thein-vitro screening test system described above is preferably below 50μM, more preferably below 25 μM and very particularly preferably below10 μM.

The compounds according to the invention are thus useful activecompounds for the treatment and prophylaxis of disorders caused byherpes viruses, in particular Herpes simplex viruses. Examples ofindication areas which may be mentioned are:

-   1) Treatment and prophylaxis of herpes infections, in particular    Herpes simplex infections in patients displaying symptoms such as    Herpes labialis, Herpes genitalis, and HSV-related keratitis,    encephalitis, pneumonia, hepatitis etc.-   2) Treatment and prophylaxis of herpes infections, in particular    Herpes simplex infections, in patients with a suppressed immune    system (for example AIDS patients, cancer patients, patients having    a genetic immunodeficiency, transplant patients)-   3) Treatment and prophylaxis of herpes infections, in particular    Herpes simplex infections, in new-born children and infants-   4) Treatment and prophylaxis of herpes infections, in particular    Herpes simplex infections, and in herpes-positive patients, in    particular Herpes-simplex-positive patients, for suppressing    recurrence (suppression therapy)    In-Vivo Action    Animals:

6 week-old female mice, BALB/cABom strain were obtained from acommercial breeder (Bomholtgard Breeding and Research Centre Ltd.).

Infection:

The animals were anaesthetized with diethyl ether (Merck) in a sealedglass vessel. 50 μl of a dilution of the virus stock (infection dose5×10⁴ Pfu) were introduced into the nose of the anaesthetized animalsusing an Eppendorf pipette. In 90-100% of the animals, this infectiondose causes death by a generalized infection with prominent respiratoryand central-nervous symptoms on average after 5 to 8 days.

Treatment and Assessment:

6 hours after the infection, the animals were treated with doses of0.1-100 mg/kg of body mass, 3 times per day, at 7 a.m., 2 p.m. and 7p.m., for a period of 5 days. The substances were pre-dissolved in DMSOand resuspended in tylose/PBS (Hoechst) (final concentration 1.5% DMSO,0.5% tylose in PBS).

After the last administration, the animals were monitored further andthe time of death was determined.

A comparison of the survival curves showed for the compound of Example57, for example, an ED₅₀ of about 0.7 mg/kg for HSV-2, where ED₅₀ meansthat 50% of the animals survive at this dose.

The novel active compounds can be converted in a known manner into thecustomary formulations, such as tablets, sugar-coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers and solvents. Here,the therapeutically active compound should in each case be present in aconcentration of about 0.5 to 90% by weight of the total mixture, i.e.in amounts which are sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example, if thediluent used is water, to use, if appropriate, organic solvents asauxiliary solvents.

Administration is carried out in a customary manner, preferably orally,parenterally or topically, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the activecompounds using suitable liquid carrier materials can be employed.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of from approximately 0.001 to 20mg/kg, preferably approximately 0.01 to 10 mg/kg, of bodyweight toachieve effective results, and in the case of oral administration thedose is approximately 0.01 to 30 mg/kg, preferably 0.1 to 20 mg/kg, ofbodyweight.

In spite of this, it may be necessary, if appropriate, to depart fromthe amounts mentioned, namely depending on the bodyweight or on the typeof administration route, on the individual response to the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide this into several individual administrations over the course ofthe day.

If appropriate, it may be useful to combine the compounds according tothe invention with other active substances, in particular antiviralactive substances.

Starting Materials

EXAMPLE I 2-Chloro-4-methyl-1,3-thiazol-5-sulphonyl chloride

At room temperature, 150 g (1.12 mol) of 2-chloro-4-methyl-1,3-thiazoleare added dropwise to a solution of 331 g (2.81 mol) of thionyl chloridein 653 g (5.61 mol) of chlorosulphonic acid. The solution is heated atreflux for 48 h. The mixture is then poured into 3 l of ice-water andextracted with 4×400 ml of dichloromethane. The combined organic phasesare washed with 2.5 l of water, dried over sodium sulphate andconcentrated. Distillation of the crude product gives 233.7 g of productin the form of an oil. (Bp 87-96° C., 0.7 mbar, GC 98.1%, yield 89.6%).

EXAMPLE II 2-Chloro-4-methyl-1,3-thiazol-5-sulphonamide

At −10° C., 117.7 g (1.8 mol) of a 26% strength aqueous ammonia solutionare added dropwise to a solution of 208 g (95% strength, 0.9 mol) of2-chloro-4-methyl-1,3-thiazole-5-sulphonyl chloride in 1000 ml oftetrahydrofuran. The mixture is stirred without further cooling for 2 hand the reaction mixture is then concentrated using a rotary evaporator.The crude product is used for the next step without furtherpurification.

EXAMPLE III 4-Methyl-2-(methylamino)-1,3-thiazole-5-sulphonamide

At room temperature, 144 g (0.576 mol) of2-chloro-4-methyl-1,3-thiazole-5-sulphonamide are initially charged in600 ml of acetonitrile, and 147 g (1.9 mol) of a 40% strength aqueousmethylamine solution are metered in at room temperature. The reactionmixture is stirred at 50° C. for 6 h and then concentrated using arotary evaporator. The residue is admixed with water, filtered off withsuction and dried.

Yield: 78 g (66%) M.p.: 194° C.

EXAMPLE IV 2-Fluorophenylboronic acid

Under argon, 155 g (0.86 mol) of 2-fluorobromobenzene are initiallycharged in 732 ml of absolute tetrahydrofuran and, at −78° C., mixedslowly with 600 ml of 1.6 M n-butyllithium in hexane. The mixture isthen stirred at −78° C. for 2 h. At −78° C., 298 ml (1.28 mol) oftrimethyl borate are then added dropwise. After 1 h, cooling is removed,and the reaction mixture is stirred overnight and warmed to roomtemperature. For work-up, the mixture is, at 0° C., mixed with 346 ml ofsaturated ammonium chloride solution, the pH is adjusted to pH 6 using1N HCl and the aqueous phase is extracted 3 times with in each case 250ml of methylene chloride. The combined organic phases are washed withsaturated sodium chloride solution and dried with magnesium sulphate.This gives Example IV in the form of a beige solid.

Yield: 60.0 g (48%) MS (EI, m/z): 140 (80%, [M]⁺), 96 (100%, [C₆H₅F]⁺)

EXAMPLE V Methyl (2′-fluoro[1,1′-biphenyl]-4-yl)acetate

Under argon, 47.6 g (0.21 mol) of methyl 4-bromophenylacetate areinitially charged in 400 ml of absolute tetrahydrofuran and, at roomtemperature, admixed with 320 ml of 1M sodium carbonate solution and 40g of (0.28 mol) of 2-fluorophenylboronic acid. 7.0 g (0.01 mol) ofbis(triphenylphosphane)palladium(II) chloride are added, and the mixtureis then heated under reflux for 18 h. After cooling, the mixture isdiluted with 500 ml of water and extracted three times with in each case300 ml of ethyl acetate. The combined organic phases are washed with ineach case 400 ml of saturated ammonium chloride solution, water andsaturated sodium chloride solution, dried over magnesium sulphate andfreed from the solvent under reduced pressure. Example V is obtainedafter silica gel filtration (petroleum ether/ethyl acetate 10:1) as acolourless oil.

Yield: 46.0 g (94%) ¹H-NMR (500 MHz, CDCl₃, δ/ppm): 3.71 (s, 2H), 3.76(s, 3H), 7.18-7.46 (m, 4H) 7.40 (d, J=8.3 Hz; 2H), 7.56 (dd, J₁=8.3 Hz,J₂=1.7 Hz; 2H).

EXAMPLE VI (2′-Fluoro[1,1′-biphenyl]4-yl)acetic acid

26.5 g (0.11 mol) of methyl (2′-fluoro[1,1′-biphenyl]-4-yl)acetate areinitially charged in 50 ml of ethanol and, at room temperature, admixedwith a solution of 12.8 g (0.19 mol) of potassium hydroxide pellets in25 ml of water. The mixture is then heated under reflux for 4 h. Aftercooling, the crude mixture is concentrated under reduced pressure, andthe residue is dissolved in 100 ml of water and acidified using conc.hydrochloric acid. The precipitate is filtered off and washed repeatedlywith water, and the solid is dried. This gives Example VI in the form ofwhite crystals.

Yield: 22.7 g (91%) M.p.: 102° C. ¹H-NMR (500 MHz, CDCl₃, δ/ppm): 3.74(s, 2H), 7.18-7.47 (m, 4H), 7.41 (d, J=8.2 Hz; 2H), 7.57 (dd, J₁=8.2 Hz,J₂=1.6 Hz; 2H).

EXAMPLE VII Methyl [4-(2-pyridinyl)phenyl]acetate

Under argon, 7.85 g (34.3 mmol) of methyl 4-bromophenylacetate areinitially charged in 95 ml of toluene and, at room temperature, admixedwith 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of2-trimethyl-stannylpyridine and 0.4 g (0.3 mmol) oftetrakis(triphenylphosphane)palladium(0). The mixture is then heatedunder reflux for 18 h. After cooling, the mixture is washed with in eachcase 100 ml of 1N hydrochloric acid and saturated sodium bicarbonatesolution. The organic phase is discarded. The acidic and the basicaqueous phase are neutralized and in each case extracted with 100 ml ofdichloromethane, and the combined organic phases are dried over sodiumsulphate and freed from the solvent under reduced pressure. Example VIIis obtained after silica gel chromatography (toluene/ethyl acetategradient 5:1-1:1) as a colourless oil.

Yield: 1.6 g (19%) ¹H-NMR (400 MHz, d⁶-DMSO, δ/ppm): 3.64 (s, 3H), 3.76(s, 2H), 7.33-7.40 (m, 1H), 7.39 (d, J=8.2 Hz; 2H), 7.86-7.90 (m, 1H),7.96 (d, J=8.0 Hz; 1H), 8.05 (d, J=8.2 Hz; 2H), 8.67 (d, J=4.2 Hz,broad; 1H).

EXAMPLE VIII [4-(2-Pyridinyl)phenyl]acetic acid

700 mg (3.11 mol) of methyl [4-(2-pyridinyl)phenyl]acetate are initiallycharged in 5 ml of tetrahydrofuran and, at room temperature, admixedwith 6.2 ml of a 1M potassium hydroxide solution in water. The mixtureis then stirred at room temperature for 18 h, most of the solvent isremoved under reduced pressure and the residue is taken up in 10 ml ofwater and adjusted to a pH of about 5 using 2N hydrochloric acid. Theaqueous phase was extracted twice, in each case with 10 ml ofdichloromethane, the combined organic phases were dried over magnesiumsulphate and the solvent was removed under reduced pressure, giving thecompound of Example VIII in the form of a solid.

Yield: 300 mg (46%) ¹H-NMR (400 MHz, d⁶-DMSO, δ/ppm): 3.76 (s, 2H),7.45-7.51 (m, 1H), 7.50 (d, J=8.3 Hz; 2H), 8.00 (td, J₁=7.7 Hz, J₂=1.9Hz; 1H), 8.07 (d, J=7.9 Hz; 1 H), 8.15 (d, J=8.3 Hz; 2H), 8.78 (dt,J₁=4.0 Hz, J₂=0.9 Hz; 1H).

PREPARATION EXAMPLES EXAMPLE 15N-[5-(Aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-2-[1,1′-biphenyl]-4-yl-N-methylacetamide

138.2 mg (0.65 mmol) of 4-biphenylacetic acid and 99.7 mg (0.65 mmol) of1-hydroxy-1H-benzotriazole hydrate are initially charged at roomtemperature in 5 ml of dimethylformamide. 150 mg (0.72 mmol) of2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 138.7 mg (0.72mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochlorideare added, and the mixture is stirred at room temperature for 72 h. Thereaction mixture is then filtered off with suction and the residue isrecrystallized from 2-propanol. This gives a white solid.

Yield: 240 mg (83.0%) M.p.: 191° C. ¹H-NMR (300 MHz, d⁶-DMSO, δ/ppm):2.47 (s, 3H; partially under the DMSO signal), 3.71 (s, 3H), 4.20 (s,2H), 7.32-7.70 (m, 11H).

EXAMPLE 38N-[5-(Aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide

At room temperature, 300 mg (1.41 mmol) of [4-(2-pyridinyl)phenyl]aceticacid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate areinitially charged in 4 ml of dimethylformamide. 307 mg (1.48 mmol) of2-methylaminomethyl-1,3-thiazole-5-sulphonamide and 284 mg (1.48 mmol)of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride areadded, and the mixture is stirred at room temperature for 18 h. Thesolvent is then removed under reduced pressure, the residue is taken upin toluene and the solvent is once more removed under reduced pressure.The residue is stirred with 15 ml of water and 3 ml of methanol and thenfiltered off, and the filtrate is re-extracted with 20 ml ofdichloromethane. Solid and dichloromethane phase are combined and thesolvent is removed under reduced pressure. This gives the compound ofExample 38 in the form of a white solid.

Yield: 440 mg (74.0%) M.p.: 188-192° C. MS (ESI, m/z): 403 (100%,[M+H]⁺) ¹H-NMR (400 MHz, d⁶-DMSO, δ/ppm): 2.38 (s, 3H; under the DMSOsignal), 3.64 (s, 3H), 4.15 (s, 2H), 7.28-7.26 (m, 1H), 7.32 (d, J=8 Hz;2H), 7.58 (s, 2H), 7.82-7.96 (m, 2H), 7.98 (d, J=8.0 Hz; 2H), 8.61 (m;1H).

EXAMPLE 57N-[5-(Aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-2-(2′-fluoro[1,1′-biphenyl]-4-yl)-N-methylacetamide

At room temperature, 17.33 g (73.3 mmol) of(2′-fluoro[1,1′-biphenyl]4-yl)acetic acid and 9.9 g (73.3 mmol) of1-hydroxy-1H-benzotriazole hydrate are initially charged in 600 ml ofdimethylformamide. 16.84 g (81.4 mmol) of2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 15.58 g (81.4mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochlorideare added, and the mixture is stirred at room temperature for 18 h. Mostof the dimethylformamide is removed at 50° C. under high vacuum, and theresidue is taken up in 400 ml of dichloromethane and then washed with ineach case 350 ml of water and 10% citric acid solution. Drying overmagnesium sulphate and removal of the solvent under reduced pressuregives the compound of Example 57 in the form of a white solid.

Yield: 23.2 g (76.0%) M.p.: 211° C. ¹H-NMR (400 MHz, CDCl₃, δ/ppm): 2.58(s, 3H), 3.73 (s, 3H), 4.07 (s, 2H), 5.91 (s, 2H), 7.13-7.46 (m, 4H),7.34 (d, J=8.1 Hz; 2H), 7.56 (d, broad, J=8.1 Hz; 2H).

EXAMPLE 87N-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-2-(2′,5′-difluoro-1,1′-biphenyl-4-yl)-N-methylacetamide

At room temperature, 1.00 g (4.0 mmol) of(2′,5′-difluoro[1,1′-biphenyl]-4-yl)acetic acid and 0.54 g (4.0 mmol) of1-hydroxy-1H-benzotriazole hydrate are initially charged in 15 ml ofdimethylformamide. 0.84 g (4.0 mmol) of2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 0.77 g (4.0 mmol)of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride areadded, and the mixture is stirred at room temperature for 18 h. Most ofthe dimethylformamide is removed at 50° C. under high vacuum, and theresidue is stirred 3 times with in each case 50 ml of water and filteredoff, stirred with 50 ml of isopropanol and filtered off once more.Removal of the solvent under reduced pressure gives the compound ofExample 87 in the form of a slightly yellow solid.

Yield: 0.83 g (47.3%) M.p.: 184° C. ¹H-NMR (400 MHz, DMSO, δ/ppm): 2.49(s, 3H), 3.71 (s, 3H), 4.24 (s, 2H), 7.22-7.46 (m, 3H), 7.38 (d, J=8.2Hz; 2H), 7.56 (d, J=8.2 Hz; 2H), 7.65 (s, 2H).

EXAMPLE 126N-[5-(Aminosulphonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(1H-pyrazol-1-yl)phenyl]acetamide

0.100 g (0.48 mmol) of2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide is dissolved in 10 mlof N,N-dimethylformamide and, at room temperature, admixed with 0.110 g(0.53 mmol) of [4-(1H-pyrazol-1-yl)phenyl]acetic acid, 0.070 g (0.53mmol) of 1-hydroxy-1H-benzotriazole and 0.070 g (0.53 mmol) ofN,N′-diisopropylcarbodiimide. The solution is stirred at roomtemperature overnight. The mixture is then poured into water and theaqueous phase is extracted 3 times with ethyl acetate. The combinedorganic phases are dried with sodium sulphate and concentrated. Thecrude product is subjected to fine purification on a preparative HPLC(RP18 column; mobile phase: acetonitrile/water gradient).

Yield: 0.11 g (59%) LC-MS (Method: SMKL-N1-1Low Vol HCl): retentiontime: 3.65 MS(ESI): 783 (2Mz+H), 392 (Mz+H). ¹H-NMR (300 MHz, DMSO,δ/ppm): 2.48 (s, 3H), 3.72 (s, 3H), 4.20 (s, 2H), 6.55 (t, J=2 Hz; 1H),7.38 (d, J=7 Hz; 2H), 7.65 (s, 2H), 7.75 (d, J=2 Hz; 1H), 7.82 (d, J=7Hz; 2H), 8.49 (d, J=2 Hz; 1H).

The compounds listed in the table below are prepared analogously to theprocedures given above:

Ex. M.p. Rf Rt [min] No. Structure [° C.] value method 1

186 2

187 3

170 4

180 5

154 6

167 7

192 8

186 9

109 10

128 11

184 12

157 13

153 14

154 15

191 16

133 17

179 18

202 19

163 20

154 21

161 22

158 23

156 24

129 25

105-106 26

142-143 27

139-140 28

oil 5.66 29

179 30

190 31

192 32

193 33

201 34

74-75 35

125-127 36

156 37

oil 0.11 CH2Cl2/ MeOH) 96:4) 38

188-192 39

208 40

177 41

200 42

270 43

125-127 44

168 45

170-172 46

 94 47

188 48

152 49

216 50

108 51

161 52

 80 53

0.30 (CH2Cl2/ MeOH 100:5) 54

160 55

130 56

113 57

211 58

230 59

202 60

145 61

190 62

219 63

68-70 64

152 65

165 66

122 67

168 68

205 69

189 70

130 71

202 72

109 73

204 74

183 75

231 76

234 77

230 78

232 79

264 80

150 81

175 82

0.13 (CH2Cl2/ MeOH/ NH3 10:1:0.1) 83

0.10 (CH2Cl2/ MeOH/ NH3 10:1:0.1) 84

202 85

3.38 86

3.1 87

184 88

215 89

138 90

180 91

193 92

136 93

161 94

117 95

154 96

174 97

159 98

203 99

202 100

209 101

167 102

 81 103

221 104

234 105

218 106

225 107

0.38 (CH2Cl2/ MeOH 100:3) 108

225 109

206 110

234 112

128 113

217 114

187 115

156 116

199 117

237 118

204 119

148 120

 79 121

223 122

0.50 (CH2Cl2/ MeOH 100:5) 123

0.57 (CH2Cl2/ MeOH 100:5) 124

4.05 125

159 126

3.65 127

3.45 128

3.1 129

0.14 (CH2Cl2/ MeOH 100:5) 130

130 131

130 132

175

In the table above, the Rf value denotes the retention index for silicagel thin-layer chromatography. SMKL-N1-1 denotes the LC-MS method below.

Method: SMKL-N1 MS unit type: Finnigan MAT 900S Ionization: ESI positiveHPLC unit type: TSP: P4000, AS3000, UV3000HR Pump head: normal Column:Symmetry C 18 150 mm × 2.1 mm 5 μm Source: Waters UV detector DAD: 210nm Oven temp.: 40° C. Gradient: Time A:% B:% C:% D:% Flow 0 10.0 45 45 —0.6 4 90 5 5 — 0.6 9 90 5 5 — 0.6 9.5 10.0 45 45 — 0.8 11.5 10.0 45 45 —0.8 12 10.0 45 45 — 0.6 A: CH₃CN B: HCl 0.01 n C: H₂O D: —

1. Compounds of the general formula (I):

in which R¹ represents hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,amino-(C_(1-C) ₆)-alkyl or halogeno-(C₁-C₆)-alkyl, R² and R³ areidentical or different and represent hydrogen, (C₁-C₆)-alkoxy,(C₃-C₈)-cycloalkyl or biphenylaminocarbonyl, or represent (C₁-C₆)-alkylwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen,hydroxyl, amino, tri-(C₁-C₆)-alkylsilyloxy, radicals of the formula

in which R^(2′) represents hydrogen or (C₁-C₄)-alkyl, a 5- or 6-memberedaromatic heterocycle having up to 3 heteroatoms from the groupconsisting of S, N and O, where a nitrogen-containing heterocycle mayalso be attached via the nitrogen atom, a 3- to 8-membered saturated orunsaturated nonaromatic heterocycle having up to 3 heteroatoms from thegroup consisting of S, N and O, which may optionally be attached via anitrogen atom, and (C₆-C₁₀)-aryl which for its part may be substitutedby hydroxyl or (C₁-C₆)-alkoxy, or represent a group of the formula

in which R⁸ and R⁹ are identical to or different from one another andrepresent hydrogen and (C₁-C₄)-alkyl, or represent a group of theformula

in which R¹⁰ is the side-group of a naturally occurring α-amino acid, orrepresent a group of the formula

in which R¹¹ represents (C₁-C₄)-alkyl and R¹² represents hydrogen,(C₁-C₄)-alkyl or represents a group of the formula

in which R^(10′) is the side-group of a naturally occurring α-aminoacid, or R² and R³ together with the nitrogen atom form a 5- or6-membered saturated heterocycle which may optionally contain an oxygenatom, R⁴ represents hydrogen, (C₁-C₆)-acyl, (C₂-C₆)-alkenyl,(C₃-C₈)-cycloalkyl, or R⁴ represents (C₁-C₆)-alkyl which may optionallybe substituted by 1 to 3 substituents selected from the group consistingof halogen, hydroxyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-acyl, (C₁-C₆)-alkoxy,carboxyl,

 in which R^(4′) represents hydrogen, —(OCH₂CH₂)_(n)OCH₂CH₃, in which nis 0 or 1, phenoxy, (C₆-C₁₀)-aryl and —NR¹³R¹⁴, in which R¹³ and R¹⁴ areidentical or different and represent hydrogen, (C₁-C₆)-acyl,(C₁-C₆)-alkyl, carbamoyl, mono- or di-(C₁-C₆)-alkylamino-(C₁-C₆)-alkyl,mono- or di-(C₁-C₆)-alkylaminocarbonyl, (C₆-C₁₀)-aryl or(C₁-C₆)-alkoxycarbonyl, or R¹³ and R¹⁴ together with the nitrogen atomform a 5- or 6-membered saturated heterocycle which may optionallycontain a further heteroatom from the group consisting of S and O or aradical of the formula —NR¹⁵, and which may be substituted by oxo, inwhich R¹⁵ represents hydrogen or (C₁-C₄)-alkyl, or R⁴ represents(C₁-C₆)-alkyl which is substituted by a 5- or 6-membered aromatic,optionally benzo-fused heterocycle having up to 3 heteroatoms from thegroup consisting of S, N and O, where a nitrogen-containing heterocyclemay also be attached via the nitrogen atom, or which is substituted byradicals of the formulae

in which R¹⁶ represents hydrogen or (C₁-C₆)-alkyl, R¹⁷ and R¹⁸ areidentical or different and represent hydrogen, (C₁-C₆)alkyl or(C₆-C₁₀)-aryl, where abovementioned (C₁-C₆)-alkyl and (C₆-C₁₀)-aryl mayoptionally be substituted by 1 to 3 substituents selected from the groupconsisting of hydroxyl, (C₁-C₆)-alkoxy and halogen, R⁵ representshydrogen, (C₁-C₆)-alkyl, halogen, amino, mono- or di-(C₁-C₆)-alkylaminoor represents (C₁-C₆)-alkanoylamino, R⁶ represents phenyl which mayoptionally be substituted by one to three substituents selected from thegroup consisting of halogen, (C₆-C₁₀)-aryl which may optionally besubstituted by 1 to 3 substituents selected from the group consisting of(C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,(C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl, carboxyl,carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono- ordi-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl,tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylthio, hydroxyl, carboxyl, partiallyfluorinated (C₁-C₆)-alkoxy having up to 6 fluorine atoms, (C₁-C₆)-alkylwhich is optionally substituted by a radical of the formula

a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe group consisting of S, N and O which may optionally be attached viaa nitrogen atom and which may optionally be substituted by 1 to 3substituents selected from the group consisting of (C₁-C₆)-alkanoyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen, (C₁-C₆)-alkoxycarbonyl, nitro,halogeno-(C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylthio, hydroxyl, carboxyl, carbamoyl, aminocarbonyl, mono-or di-(C₁-C₆)-alkylaminocarbonyl, mono- or di-(C₁-C₆)-alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkylsulphoxy,(C₁-C₆)-alkylsuphonyl, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O which may optionally be attachedvia a nitrogen atom, and/or cyano, a 3- to 8-membered saturated orunsaturated non-aromatic mono- or bicyclic heterocycle having up to 3heteroatoms from the group consisting of S, N and O, which mayoptionally be attached via a nitrogen atom and which may optionally besubstituted by 1 to 3 substituents selected from the group consisting ofoxo, halogen, hydroxyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkyl andhydroxy-(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl and groups of the formulae —OR¹⁹,—NR²⁰R²¹ or —CO—NR²²R²³, carbazole, dibenzofuran or dibenzothiophene,xanthene or 9,10-dihydroacridine, in which R¹⁹ is phenyl which for itspart is optionally substituted by a group of the formula —NR²⁴R²⁵ inwhich R²⁴ and R²⁵ are identical or different and represent hydrogen,(C₁-C₆)-alkyl or (C₁-C₆)-acyl, or R¹⁹ represents (C₁-C₆)-alkyl which isoptionally mono- to trisubstituted by hydroxyl and/or halogen, R²⁰ andR²¹ are identical or different and represent hydrogen, carbamoyl, mono-or di-(C₁-C₆)-alkylaminocarbonyl, phenyl, (C₁-C₆)-acyl or (C₁-C₆)-alkyl,where abovementioned (C₁-C₆)-alkyl is optionally substituted by(C₁-C₆)-alkoxy, (C₁-C₆)-acyl, by phenyl or by a 5- or 6-memberedaromatic heterocycle having up to 3 heteroatoms from the groupconsisting of S, N and O, where abovementioned phenyl and abovementionedaromatic heterocycle are optionally mono- to trisubstituted by identicalor different substituents from the group consisting of halogen andhydroxyl, and R²² and R²³ are identical or different and representhydrogen or (C₁-C₆)-alkyl, and R⁷ may have the meaning of R⁵ and may beidentical to or different from R⁵, and their salts.
 2. Compounds of thegeneral formula (I) according to claim 1:

in which R¹ represents hydrogen, halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,amino-(C₁-C₆)-alkyl or halogeno-(C₁-C₆)-alkyl, R² and R³ are identicalor different and represent hydrogen, (C₁-C₆)-alkoxy, (C₃-C₈)-cycloalkylor biphenylaminocarbonyl, or represent (C₁-C₆)-alkyl which is optionallysubstituted by 1 to 3 substituents selected from the group consisting of(C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen, hydroxyl, amino, radicalsof the formula

a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe group consisting of S, N and O, where a nitrogen-containingheterocycle may also be attached via the nitrogen atom, a 3- to8-membered saturated or unsaturated nonaromatic heterocycle having up to3 heteroatoms from the group consisting of S, N and O, which mayoptionally be attached via a nitrogen atom, and (C₆-C₁₀)-aryl, which forits part may be substituted by hydroxyl or (C₁-C₆)-alkoxy, or representa group of the formula

in which R⁸ and R⁹ are identical to or different from one another andrepresent hydrogen and (C₁-C₄)-alkyl, or represent a group of theformula

in which R¹⁰ is the side-group of a naturally occurring α-amino acid, orrepresent a group of the formula

in which R¹¹ represents (C₁-C₄)-alkyl and R¹² represents hydrogen,(C₁-C₄)-alkyl or represents a group of the formula

in which R^(10′) is the side-group of a naturally occurring α-aminoacid, or R² and R³ together with the nitrogen atom form a 5- or6-membered saturated heterocycle which may optionally contain an oxygenatom, R⁴ represents hydrogen, (C₁-C₆)-acyl, (C₂-C₆)-alkenyl,(C₃-C₈)-cycloalkyl, or R⁴ represents (C₁-C₆)-alkyl which may optionallybe substituted by 1 to 3 substituents selected from the group consistingof halogen, hydroxyl, (C₁-C₆)-acyl, (C₁-C₆)alkoxy,—(OCH₂CH₂)_(n)OCH₂CH₃, in which n is 0 or 1, phenoxy, (C₆-C₁₀)-aryl and—NR³R¹⁴, in which R¹³ and R¹⁴ are identical or different and representhydrogen, (C₁-C₆)-acyl, (C₁-C₆)-alkyl, carbamoyl, mono- ordi-(C₁-C₆)-alkylamino-(C₁-C₆)-alkyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, (C₆-C₁₀)-aryl or (C₁-C₆)-alkoxycarbonyl,or R¹³ and R¹⁴ together with the nitrogen atom form a 5- or 6-memberedsaturated heterocycle which may optionally contain a further heteroatomfrom the group consisting of S and O or a radical of the formula —NR¹⁵and which may be substituted by oxo, in which R¹⁵ represents hydrogen or(C₁-C₄)-alkyl, or R⁴ represents (C₁-C₆)-alkyl which is substituted by a5- or 6-membered aromatic, optionally benzo-fused heterocycle having upto 3 heteroatoms from the group consisting of S, N and O, where anitrogen-containing heterocycle may also be attached via the nitrogenatom, or which is substituted by radicals of the formulae

in which R¹⁶ represents hydrogen or (C₁-C₆)-alkyl, R¹⁷ and R¹⁸ areidentical or different and represent hydrogen, (C₁-C₆)-alkyl or(C₆-C₁₀)-aryl, where abovementioned (C₁-C₆)-alkyl and (C₆-C₁₀)-aryl mayoptionally be substituted by 1 to 3 substituents selected from the groupconsisting of hydroxyl, (C₁-C₆)-alkoxy and halogen, R⁵ representshydrogen, (C₁-C₆)-alkyl, halogen, amino, mono- or di-(C₁-C₆)-alkylaminoor represents (C₁-C₆)-alkanoylamino, R⁶ represents phenyl which mayoptionally be substituted by one to three substituents selected from thegroup consisting of halogen, (C₆-C₁₀)-aryl which may optionally besubstituted by 1 to 3 substituents selected from the group consisting of(C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,(C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,halogeno-(C₁-C₆)-alkoxy, amino, (C₁-C6)-alkylthio, hydroxyl, carboxyl,carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono- ordi-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl,tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylthio, hydroxyl, carboxyl, partiallyfluorinated (C₁-C₆)-alkoxy having up to 6 fluorine atoms, (C₁-C₆)-alkylwhich is optionally substituted by a radical of the formula

a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe group consisting of S, N and O which may optionally be attached viaa nitrogen atom and which may optionally be substituted by 1 to 3substituents selected from the group consisting of (C₁-C₆)-alkanoyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen, (C₁-C₆)-alkoxycarbonyl, nitro,halogeno-(C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylthio, hydroxyl, carboxyl, carbamoyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, mono- or di-(C₁-C₆)alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkylsulphoxy,(C₁-C₆)-alkylsuphonyl, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O which may optionally be attachedvia a nitrogen atom, and/or cyano, a 3- to 8-membered saturated- orunsaturated non-aromatic mono- or bicyclic heterocycle having up to 3heteroatoms from the group consisting of S, N and O, which mayoptionally be attached via a nitrogen atom and which may optionally besubstituted by 1 to 3 substituents selected from the group consisting ofoxo, halogen, hydroxyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkyl andhydroxy-(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl and groups of the formulae —OR¹⁹,—NR²⁰R²¹ or —CO—NR²²R²³, in which R¹⁹ is phenyl which for its part isoptionally substituted by a group of the formula —NR²⁴R²⁵, in which R²⁴and R²⁵ are identical or different and represent hydrogen, (C₁-C₆)-alkylor (C₁-C₆)-acyl, or R¹⁹ represents (C₁-C₆)-alkyl which is optionallymono- to trisubstituted by hydroxyl and/or halogen, R²⁰ and R²¹ areidentical or different and represent hydrogen, carbamoyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, phenyl, (C₁-C₆)-acyl or (C₁-C₆)-alkyl,where abovementioned (C₁-C₆)-alkyl is optionally substituted by(C₁-C₆)-alkoxy, (C₁-C₆)-acyl, by phenyl or by a 5- or 6-memberedaromatic heterocycle having up to 3 heteroatoms from the groupconsisting of S, N and O, where abovementioned phenyl and abovementionedaromatic heterocycle are optionally mono- to trisubstituted by identicalor different substituents from the group consisting of halogen andhydroxyl, and R²² and R²³ are identical or different and representhydrogen or (C₁-C₆)-alkyl, and R⁷ may have the meaning of R⁵ and may beidentical to or different from R⁵, and their salts.
 3. Compounds of thegeneral formula (I) according to claim 1 or 2, in which R¹ representshydrogen or (C₁-C₆)-alkyl.
 4. Compounds of the general formula (I)according to claim 1, in which R² and R³ each independently representhydrogen or (C₁-C₆)-alkyl.
 5. Compounds of the general formula (I)according to claim 1,in which R⁴ represents hydrogen or (C₁-C₆)-alkyl.6. Compounds of the general formula (I) according to claim 1, in whichR⁵ represents hydrogen.
 7. Compounds of the general formula (I)according to claim 1, in which R⁶ represents phenyl which may optionallybe substituted by one to three substituents selected from the groupconsisting of halogen, (C₆-C₁₀)-aryl which may optionally be substitutedby 1 to 3 substituents selected from the group consisting of(C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,(C₁-C₆)-alkoxycarbonyl, nitro, halogeno-(C₁-C₆)-alkyl,halogeno-(C₁-C₆)-alkoxy, amino, hydroxyl, mono- ordi-(C₁-C₆)-alkylamino, mono- or di-(C₁-C₆)-alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, and/or cyano, and a 5- or 6-memberedaromatic heterocycle having up to 3 heteroatoms from the groupconsisting of S, N and O, which may optionally be attached via anitrogen atom.
 8. Compounds according to claim 1 having the followingformula:

in which R¹, R², R³, R⁴, R⁵ and R⁷ are each as defined in claim 1, R²⁶and R²⁷ are identical or different and represent hydrogen, halogen,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylthio, hydroxyl,carboxyl, partially fluorinated (C₁-C₆)-alkoxy having up to 6 fluorineatoms, (C₁-C₆)-alkyl, a group of the formulae —OR⁹, —NR²⁰R²¹ or —CO—NR²²R²³, in which R¹⁹ represents phenyl which for its part is optionallysubstituted by a group of the formula —NR²⁴R²⁵, in which R²⁴ and R²⁵ areidentical or different and represent hydrogen, (C₁-C₆)-alkyl or(C₁-C₆)-acyl, or R¹⁹ represents (C₁-C₆)-alkyl which is optionally mono-to trisubstituted by hydroxyl and/or halogen, R²⁰ and R²¹ are identicalor different and represent hydrogen, carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, phenyl, (C₁-C₆)-acyl or (C₁-C₆)-alkyl,where abovementioned (C₁-C₆)-alkyl is optionally substituted by(C₁-C₆)-alkoxy, (C₁-C₆)-acyl, phenyl or by a 5- or 6-membered aromaticheterocycle having up to 3 heteroatoms from the group consisting of S, Nand O, where abovementioned phenyl and abovementioned aromaticheterocycle are optionally mono- to trisubstituted by identical ordifferent substituents from the group consisting of halogen andhydroxyl, and R²² and R²³ are identical or different and representhydrogen or (C₁-C₆)-alkyl, R²⁸ represents (C₆-C₁₀)-aryl, which mayoptionally be substituted by 1 to 3 substituents selected from the groupconsisting of (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,(C₁-C₆)-alkoxycarbonyl, nitro, halogen-(C₁-C₆)-alkyl,halogen-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl, carboxyl,carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono- ordi-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl,tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, or R²⁸ represents a 5- or6-membered aromatic heterocycle having up to 3 heteroatoms from thegroup consisting of S, N and O, which may optionally be attached via anitrogen atom and which may optionally be substituted by 1 to 3substituents selected from the group consisting of (C₁-C₆)-alkanoyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen, (C₁-C₆)-alkoxycarbonyl, nitro,halogeno-(C₁-C₆)-alkyl, halogeno-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylthio, hydroxyl, carboxyl, carbamoyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, mono- or di-(C₁-C₆)-alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkylsulphoxy,(C₁-C₆)-alkylsulphonyl, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, and their salts.
 9. Compoundaccording to claim 1 of the formula:

and pharmaceutically acceptable salts thereof.
 10. Compound according toclaim 1 of the formula:

and pharmaceutically acceptable salts thereof.
 11. Compound according toclaim 1 of the formula:

and pharmaceutically acceptable salts thereof.
 12. Compound according toclaim 1 of the formula:


13. Compound according to claim 1 of the formula:


14. Compounds of the general formula (IV)

in which R¹, R⁴, R⁵, R⁶ and R⁷ are each as defined in claim 1 and D is ahalogen atom.
 15. Process for preparing the compounds of the generalformula (I) according to claim 1, characterized in that [A] compounds ofthe general formula (II)

in which R¹, R², R³ and R⁴ are each as defined in claim 1, are reactedwith compounds of the general formula (III)

in which A represents a leaving group and R⁵, R⁶ and R⁷ are each asdefined in claim 1, in inert solvents, or [B] compounds of the generalformula (IV)

in which R¹, R⁴, R⁵, R⁶ and R⁷ are each as defined in claim 1 and D is ahalogen atom, are reacted with amines of the general formula (V),HNR²R³  (v) in which R² and R³ are each as defined in claim 1, in inertsolvents, or [C] compounds of the general formula (X)

in which R¹, R², R³, R⁴, R⁵, and R⁷ are each as defined in claim 1, R²⁶and R²⁷ are identical or different and represent hydrogen, halogen,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylthio, hydroxyl,carboxyl, partially fluorinated (C₁-C₆)-alkoxy having up to 6 fluorineatoms, (C₁-C₆)-alkyl, a group of the formulae —OR¹⁹, —NR²⁰R²¹ or—CO—NR²²R²³, in which R¹⁹ represents phenyl which for its part isoptionally substituted by a group of the formula —NR²⁴R²⁵, in which R²⁴and R²⁵ are identical or different and represent hydrogen (C₁-C₆) or(C₁-C₆)-acyl, or R¹⁹ represents (C₁-C₆)-alkyl which is optionally mono-to trisubstituted by hydroxyl and/or halogen, R²⁰ and R²¹ are identicalor different and represent hydrogen, carbamoyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, phenyl, (C₁-C₆)-acyl or (C₁-C₆)alkyl,where abovementioned (C₁-C₆)-alkyl is optionally substituted by(C₁-C₆)-alkoxy, (C₁-C₆)-acyl, phenyl or by a 5- or 6-membered aromaticheterocycle having up to 3 heteroatoms from the group consisting of S. Nand O, where abovementioned phenyl and abovementioned aromaticheterocycle are optionally mono- to trisubstituted by identical ordifferent substituents from the group consisting of halogen andhydroxyl, and R²² and R²³ are identical or different and representhydrogen or (C₁-C₆)-alkyl, and E is trifluoromethanesulphonate orhalogen, are reacted with boronic acids or stannanes of the generalformula (Xl):R²⁸M  (Xl), in which R²⁸ represents (C₆-C₁₀)-aryl, which may optionallybe substituted by 1 to 3 substituents selected from the group consistingof (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen,(C₁-C₆)-alkoxycarbonyl, nitro, halogen-(C₁-C₆)-alkyl,halogen-(C₁-C₆)-alkoxy, amino, (C₁-C₆)-alkylthio, hydroxyl, carboxyl,carbamoyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, mono- ordi-(C₁-C₆)-alkanoylamino, (C₁-C₆)-alkoxycarbonylamino,(C₁-C₆)-alkylsulphoxy, (C₁-C₆)-alkylsulphonyl.tri-(C₁-C₆)-alkylsilyloxy, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, or R²⁸ represents a 5- or6-membered aromatic heterocycle having up to 3 heteroatoms from thegroup consisting of S, N and O, which may optionally be attached via anitrogen atom and which may optionally be substituted by 1 to 3substituents selected from the group consisting of (C₁-C₆)-alkanoyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, halogen, (C₁-C₆)-alkoxycarbonyl, nitro,halogeno-(C₁-C₆)alkyl, halogeno-(C₁-C₆)-alkoxy, amino,(C₁-C₆)-alkylthio, hydroxyl, carboxyl, carbamoyl, mono- ordi-(C₁-C₆)-alkylaminocarbonyl, mono- or di-(C₁-C₆)-alkanoylamino,(C₁-C₆)-alkoxycarbonylamino, (C₁-C₆)-alkylsulphoxy,(C₁-C₆)-alkylsulphonyl, a 3- to 8-membered saturated or unsaturatednonaromatic mono- or bicyclic heterocycle having up to 3 heteroatomsfrom the group consisting of S, N and O, which may optionally beattached via a nitrogen atom, and/or cyano, and M is atri-(C₁-C₆)-alkylstannyl group or a boronic acid group, in inertsolvents in the presence of palladium catalysts at temperatures of50-140° C., to give compounds of the formula (XIV)

or [D] compounds of the general formula (XII)

in which R¹, R², R³, R⁴, R⁵, R⁷, R²⁶ and R²⁷ are each as defined aboveand M is as defined above, are reacted with trifluoromethanesulphonatesor halides of the general formula (XIII):R²⁸E  (XIII), in which R²⁸ is as defined above and E is as defined abovein inert solvents in the presence of palladium catalysts at temperaturesof 50-140° C., to give compounds of the formula (XIV). 16.Pharmaceutical composition, comprising a compound of the general formula(I) according to claim 1 in a mixture with a pharmaceutically acceptablecarrier or excipient.
 17. A method of treating viral infection,comprising administering to a human or animal an effective amount of acompound of the general formula (I) according to claim
 1. 18. The methodof claim 17, wherein said viral infection is caused by herpes viruses.19. The method of claim 17, wherein said viral infection is caused byHerpes simplex viruses.